In 1929, Philadelphia architect George Howe invited Lescaze to form a partnership, which was named Howe & Lescaze. Within just a few weeks after joining forces, the duo began work on a large project for downtown Philadelphia. The resulting structure, completed in 1932, was the Philadelphia Savings Fund Society (PSFS) Building, which is today generally considered the first International Modernistskyscraper, and the first International Style building of wide significance in the United States. Lescaze is generally given credit for the design: letters from Howe to Lescaze quote the former insisting to the latter that "the design is definitely yours." The structure replaced the bank's former headquarters in Philadelphia, a classicist structure near Washington Square built in 1897.

Lescaze submitted a design for the proposed Museum of Modern Art in New York, in 1932.[1] The wood and metal model was donated to the MOMA in 1994.

His 1937 Alfred Loomis house in Tuxedo Park, NY is regarded as an early experiment in double-skin facade construction.[2] In 1939 he designed a futuristic "House for 2089" which included a helipad on the roof.[3]